A positioned +1 nucleosome enhances promoter-proximal pausing

Nucleic Acids Res. 2015 Mar 31;43(6):3068-78. doi: 10.1093/nar/gkv149. Epub 2015 Mar 3.

Abstract

Chromatin distribution is not uniform along the human genome. In most genes there is a promoter-associated nucleosome free region (NFR) followed by an array of nucleosomes towards the gene body in which the first (+1) nucleosome is strongly positioned. The function of this characteristic chromatin distribution in transcription is not fully understood. Here we show in vivo that the +1 nucleosome plays a role in modulating RNA polymerase II (RNAPII) promoter-proximal pausing. When a +1 nucleosome is strongly positioned, elongating RNAPII has a tendency to stall at the promoter-proximal region, recruits more negative elongation factor (NELF) and produces less mRNA. The nucleosome-induced pause favors pre-mRNA quality control by promoting the addition of the cap to the nascent RNA. Moreover, the uncapped RNAs produced in the absence of a positioned nucleosome are degraded by the 5'-3' exonuclease XRN2. Interestingly, reducing the levels of the chromatin remodeler ISWI factor SNF2H decreases +1 nucleosome positioning and increases RNAPII pause release. This work demonstrates a function for +1 nucleosome in regulation of transcription elongation, pre-mRNA processing and gene expression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphatases / metabolism
  • Animals
  • Chromatin Assembly and Disassembly
  • Chromosomal Proteins, Non-Histone / metabolism
  • Exoribonucleases / metabolism
  • Genes, myc
  • Genome, Human
  • HEK293 Cells
  • Humans
  • Mice
  • Nucleosomes / genetics*
  • Nucleosomes / metabolism*
  • Promoter Regions, Genetic*
  • RNA Caps / genetics
  • RNA Caps / metabolism
  • RNA Polymerase II / metabolism
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Transcription Factors / metabolism

Substances

  • Chromosomal Proteins, Non-Histone
  • Nucleosomes
  • RNA Caps
  • RNA, Messenger
  • Transcription Factors
  • negative elongation factor
  • RNA Polymerase II
  • Exoribonucleases
  • XRN2 protein, human
  • Adenosine Triphosphatases
  • SMARCA5 protein, human